Chemokine-mediated activation of
G protein-coupled receptors CXCR1/2 promotes
tumor growth, invasion,
inflammation and
metastasis.
Repertaxin, a CXCR1/2 small-molecule inhibitor, has been shown to attenuate many of these
tumor-associated processes. The present study aimed to investigate the effects of
repertaxin alone and in combination with
5-fluorouracil (5-FU) on the malignant behavior of
gastric cancer and the potential mechanisms.
Gastric cancer MKN45 cells were treated in vitro with
repertaxin and
5-FU, either alone or in combination. MTT and colony formation assay were performed to assess proliferation. Cell cycle progression and apoptosis was completed by flow cytometry. Migration and invasion were also assessed by transwell and wound-healing assay. Western blot analysis and quantitative RT-PCR were performed to determine expression of signaling molecules. MKN45 cells were also grown as xenografts in nude mice. Mice were treated with
repertaxin and
5-FU, and
tumor volume and weight, angiogenesis, proliferation and apoptosis were monitored. Combination of
repertaxin and
5-FU inhibited MKN45 cell proliferation and increased apoptosis better than either agent alone. Similarly, enhanced effect of the combination was also observed in migration and invasion assays. The improved effect of
repertaxin and
5-FU was also observed in vivo, as xenograft models treated with both compounds exhibited significantly decreased
tumor volume and increased apoptosis. In conclusion,
repertaxin inhibited malignant behavior of human
gastric cancer MKN45 cells in vitro and in vivo and enhances efficacy of
5-fluorouracil. These data provide rationale that targeting CXCR1/2 with small molecule inhibitors may enhance chemotherapeutic efficacy for the treatment of
gastric cancer.